BACKGROUND: Osteoarthritis (OA) is a chronic progressive illness for which effective therapy is needed. We hypothesize that periarticular factors such as body fatness and muscle function are important determinants of mobility function, and also the development of knee OA, and that muscle function is compromised by local but not systemic inflammation. Basic Research: We conducted an ACUC approved experiment to determine the individual and combined effects of arthritis and hind-limb unloading on skeletal muscle function assessed by contractile force and by 31P NMR spectroscopy, and to also explore the associations between muscle function and local inflammatory mediators. Female 3-4 month old F344 rats were induced to develop (1) arthritis (CIA n= 9) by collagen injection; (2) muscle atrophy by hind-limb unloading (HU n= 7); (3) both arthritis and atrophy (CH n=5) and compared to (4) controls (CTL n=9). Animals underwent NMR spectroscopy to determine the [PCr/(PCr+Pi)] ratio reflective of muscle energy stores. This ratio during exercise and early recovery differed between the CIA and HU groups (p < 0.05). The CH group was the slowest to recover to baseline, and differed significantly from the HU group. Although the CIA and CH groups demonstrated force characteristics that did not differ significantly, differences were observed between CIA and HU groups (p < 0.05) (7). Blood and muscle samples acquired upon completion of the NMR procedure were tested for interleukins (IL)-1, -6, tumor necrosis factor (TNF)-alpha and interferon (IFN)-gamma by ELISA (Biosource). Although right and left muscle cytokine levels were well correlated (r >0.70; p < 0.05), serum levels did not predict muscle levels of the above cytokines (8). Mean IFN-gamma level was significantly lower in the CIA (25.80 mcg/ml) and HU groups (81.62 mcg/ml) than CTLs (99.1 mcg/ml), and lowest in the CH group (17.49 mcg/ml). Mean IL-6 level was significantly lower in the combined CH group (16.96 mcg/ml) than CTLs (68.78 mcg/ml). The groups did not differ significantly with regard to serum cytokine levels. We conclude from this experiment that arthritis and atrophy result in bioenergetically, and immunologically distinct muscle characteristics. We also conclude that bioenergetic recovery from exercise is most impaired with combined arthritis and atrophy. These characteristics correspond to observed group differences in muscle, but not serum levels of IFN-gamma and IL-6. Clinical Research Studies of knee OA: We embarked on 2 independent clinical studies in the past year to determine whether muscle strength, mass and function important determinants of mobility function in adults with knee OA, and if these characteristics are associated with inflammatory biomarkers. conducted an intervention trial in collaboration with faculty members of the Johns Hopkins University School of Nursing to determine the feasibility and efficacy of a home-based neuromuscular electrical stimulation (NMES) treatment to the quadriceps femoris (QF) on muscle strength, physical activity, physical performance and pain severity in older adults with knee osteoarthritis (OA) beyond an arthritis self-management course (EDU) (n=34). The stimulated knee-extensor showed a 9.1% increase in isokinetic strength over the 12-week trial compared to a 7% loss in the EDU group (time X group interaction p=0.04). Mobility performance also improved in the NMES group compared to EDU, while severity of pain reported did not. From this study we conclude that muscle strength is an important determinant of mobility function in adults with knee OA, and that a home-based NMES is a feasible intervention capable of improving muscle strength and performance in adults with knee OA without exacerbating pain. We are recruiting participants for a case-control study investigating inflammatory mediators of muscle malfunction that accompanies osteoarthritis of the knee. Thus far we have enrolled 7 OA subjects (3 men, 4 women) and 4 control subjects (2 men, 2 women) of comparable age and activity level. Blood and muscle biopsy samples will be evaluated for inflammatory and OA-related biomarkers. Muscle strength, muscle mass and mobility function will be correlated with biomarkers, and compared between the two groups. Recruitment will continue through the next year. IMPLICATIONS: If the results of these investigations support our hypotheses, a reorientation of treatment goals will be appropriate and needed to properly manage osteoarthritis of the knee. This will then lead to rational treatment strategies that will be effective in preventing loss of function in older adults with this increasingly common disease.